The Prospective Huntington At Risk Observational Study (PHAROS) was initiated by the Huntington Study Group (HSG) in 1999 to characterize and measure the clinical onset of Huntington?s disease (HD) in a diverse cohort of individuals who are at immediate risk (50:50) for having inherited the HD gene. Participants include healthy adults, age 30-55 years, who have not undergone testing for the HD gene and who wish to remain unaware of their HD gene status, yet are interested in contributing to knowledge about HD through research. Under a stringent arrangement that conceals genetic information, a blood sample is obtained from participants to measure the cytosine-adenine-guanine trinucleotide repeat (GAG) of the HD gene. Standardized clinical assessments are carried out at about 9-month intervals for up to 7 years of prospective observation by investigators who are also kept unaware of HD gene status in order to define early, HD-gene specific signs predictive of manifest disease. Nearly 500 research participants have already been enrolled in PHAROS at 36 sites in the U.S. and 6 in Canada. We plan to enroll the entire cohort of 1000 participants by November 2001, and request prospective follow up of all PHAROS participants to a planned conclusion in 2006. PHAROS will provide objective knowledge about the positive predictive value and reliability of early clinical signs of HD and their relationship to CAG and other genetic and environmental modifiers. Only 3 percent of adults in the U.S. who are at immediate risk to develop HD have chosen to undergo presymptomatic predictive testing for the HD gene, but relatively little is known about the 97 percent who have not. PHAROS will lead to an understanding of the feasibility, psychosocial, ethical, confidentiality and legal issues relevant to this under-studied majority of at-risk individuals who have chosen not to learn of their HD fate. Collectively, completion of PHAROS will: 1) refine the relationship between clinical predictors of HD onset and CAG, 2) help identify other genetic and environmental modifiers of HD onset, 3) enhance the feasibility, safety, efficiency, ethical conduct and success of preventive trials aimed at delaying HD onset, and 4) provide new insights for and improve care of individuals who risk developing this fatal neurogenetic disorder.